1. Field of the Invention
The present invention relates a to a novel 5-amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid derivative, its stereoisomer and a pharmacologically acceptable salt thereof which have an excellent antibacterial activity and to the method of preparation thereof. The present invention also relates to a pharmaceutical composition comprising an effective amount of the derivative which is useful in the treatment of infectious disease, and it also relates to a method of treatment and to synthetic intermediates.
2. Description of the Prior Art
Ciprofloxacin is a well documented antibacterial agent with a quinoline nucleus in which a cyclopropyl group occupies position 1 (The Merck Index, 11th Edition, 2315).
Efforts to improve ciprofloxacin have included preparations of numerous substituents at positions 5, 7 and 8, however the present invention relates to the first preparation to date of a quinolone compound with an amino group at position 5 and a methyl group at position 8 in combination with a pyrrolidinyl group at position 7.
To date, the antibacterial activity of quinolone compounds has either been insufficient or when sufficient has been accompanied by severe adverse reactions such as phototoxicity, chromosomal aberration, convulsions, etc. and so these latter agents have posed safety problems.
The following citations document the above problems of the quinolone antibacterial agents:
1) "Quinolone Antimicrobial Agents", 2nd Edition, Chapter 26, ed. by D.C. Hooper and J. S. Wolfson, American Society for Microbiology, Washington D.C., 1993, p.489 (concerned with phototoxicity, chromosomal aberration, convulsions, etc.)
2) Mutagenicity Tests, 2 (3), p.154 (1993) (Chromosomal aberrations, etc.)
3) Environ. Mol. Mutagen., 13, p.238 (1989) (Chromosomal aberrations, etc.)
The following outlines the relation of particular characteristics of the substituents used at the individual positions with the above problems. For instance, it is understood that the placing of a relatively bulky substituent such as a chlorine atom or methyl group at position 8 of the quinoline nucleus is desirable for the antibacterial activity, but many of the compounds which have a chlorine atom as the substituent at position 8 give rise to severe adverse reactions such a phototoxicity or chromosomal aberrations, etc. while compounds with a methyl substituent give rise to severe adverse reactions such as chromosomal aberrations, etc. Such compounds pose great problems with regard to their safety.
A substituent widely used for position 5 is an amino group, a halogen atom or a methyl group, etc., but such a substituent has the disadvantage of reducing antibacterial activity or else they also give rise to severe adverse reactions such a phototoxicity, chromosomal aberrations, etc. and so pose safety problems.
Further, at position 7 the use of a piperazinyl group does not produce sufficient antibacterial activity, while the use of a 3-aminopyrrolidinyl group, which has sufficient antibacterial activity, gives rise to severe adverse reactions such as chromosomal aberrations, etc. and so again there are safety problems.